OMNIO105PRV
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`SHORT-WAVE INFRARED SUPER-CONTINUUM LASERS FOR DETECTING
`COUNTERFEIT OR ILLICIT DRUGS AND PHARMACEUTICAL PROCESS CONTROL
`
`TECHNICAL FIELD
`
`[0001]
`
`This disclosure relates to lasers and light sources for remote or stand-off identification
`
`of counterfeit drugs, detection of illicit drugs, or process control in the pharmaceutical industry
`
`including systems and methods for using near-infrared or short-wave infrared light sources for
`
`remote detection of counterfeit or illicit drugs and process control at remote or stand-off distances in
`
`the pharmaceutical industry.
`
`BACKGROUND AND SUMMARY
`
`[0002]
`
`Counterfeiting of pharmaceuticals is a significant issue in the healthcare community
`
`as well as for the pharmaceutical industry worldwide. For example, according to the World Health
`
`Organization, in 2006 the market for counterfeit drugs worldwide was estimated at around $43
`
`Billion. Moreover, the use of counterfeit medicines may result in treatment failure or even death.
`
`For instance, in 1995 dozens of children in Haiti and Nigeria died after taking counterfeit medicinal
`
`syrups that contained diethylene glycol, an industrial solvent. As another example, in Asia one
`
`report estimated that 90% of Viagra sold in Shanghai, China, was counterfeit. With more
`
`pharmaceuticals being purchased through the internet, the problem of counterfeit drugs coming from
`
`across the borders into the United States has been growingrapidly.
`
`[0003]
`
`A rapid, non-destructive, non-contact optical method for screening or identification of
`
`counterfeit pharmaceuticals is needed. Spectroscopy using near-infrared or short-wave infrared
`
`(SWIR)
`
`light may provide such a method, because most pharmaceuticals comprise organic
`
`compounds that have overtone or combination absorption bands in this wavelength range (e.g.,
`
`between approximately 1-2.5 microns). Moreover, most drug packaging materials are at least
`
`partially transparent in the near-infrared or SWIR, so that drug compositions may be detected and
`
`identified through the packaging non-destructively. Also, using a near-infrared or SWIR light
`
`source with a spatially coherent beam permits screening at stand-off or remote distances. Beyond
`
`Petitioner Apple Inc. — Ex. 1015, p. 1
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`Petitioner Apple Inc. – Ex. 1015, p. 1
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`identifying counterfeit drugs,
`
`the near-infrared or SWIR spectroscopy may have many other
`
`beneficial applications. For example, spectroscopy may be used for rapid screening of illicit drugs
`
`or to implement process analytical technology in pharmaceutical manufacturing. There are also a
`
`wide array of applications in assessment of quality in the food industry, including screening offruit,
`
`vegetables, grains and meats.
`
`[0004]
`
`In one embodiment, a near-infrared or SWIR super-continuum (SC) source may be
`
`used as the light source for spectroscopy, active remote sensing, or hyper-spectral imaging. One
`
`embodiment of the SWIR light source may be an all-fiber integrated SWIR SC source, which
`
`leverages
`
`the mature technologies
`
`from the telecommunications and fiber optics
`
`industry.
`
`Exemplary fiber-based super-continuum sources may emit
`
`light
`
`in the near-infrared or SWIR
`
`between approximately 1.4-1.8 microns, 2-2.5 microns, 1.4-2.4 microns, 1-1.8 microns, or any
`
`number of other bands.
`
`In particular embodiments,
`
`the detection system may be a dispersive
`
`spectrometer, a Fourier transform infrared spectrometer, or a hyper-spectral imaging detector or
`
`camera.
`
`In addition, reflection or diffuse reflection light spectroscopy may be implemented using
`
`the SWIR light source, where the spectral reflectance can be the ratio of reflected energy to incident
`
`energy as a function of wavelength.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0005]
`
`For a more complete understanding of the present disclosure, and for further features
`
`and advantages thereof, reference is now made to the following description taken in conjunction
`
`with the accompanying drawings, in which:
`
`[0006]
`
`FIGURE 1
`
`shows the absorbance for two common plastics, polyethylene and
`
`polystyrene.
`
`[0007]
`
`FIGURE 2 illustrates one example of the difference in near-infrared spectrum
`
`between an authentic tablet and a counterfeit tablet.
`
`[0008]
`
`FIGURE3 showsthe second derivative of the spectral comparison of Prozac and a
`
`similarly formulated generic.
`
`Petitioner Apple Inc. — Ex. 1015, p. 2
`
`Petitioner Apple Inc. – Ex. 1015, p. 2
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`OMNIO105PRV
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`[0009]
`
`FIGURE4 illustrates an example of the near infrared spectra for different pure
`
`componentsof a studied drug.
`
`[0010]
`
`FIGURE5 shows the mid-wave infrared and long-waveinfrared absorption spectra
`
`for variousillicit drugs.
`
`[0011]
`
`FIGURE 6 showsthe absorbance versus wavelength in the near-infrared region for
`
`four classesofillegal drugs.
`
`[0012]
`
`samples.
`
`FIGURE 7 illustrates the diffuse reflectance near-infrared spectrum of heroin
`
`[0013]
`
`FIGURE8 illustrates the diffuse reflectance near-infrared spectra of different seized
`
`illicit drugs containing heroin of different concentrations, along with the spectrum for pure heroin.
`
`[0014]
`
`heroin.
`
`FIGURE9 lists possible band assignments for the various spectral features in pure
`
`[0015]
`
`FIGURE 10
`
`shows
`
`the diffuse reflectance near-infrared spectra of different
`
`compoundsthat may be frequently employed as cutting agents.
`
`[0016]
`
`FIGURE 11 provides one example of a flow-chart
`
`in the process analytical
`
`technology for the pharmaceutical industry.
`
`[0017]
`
`FIGURE12 illustrates the typical near-infrared spectra of a variety of excipients.
`
`[0018]
`
`FIGURE 13
`
`exemplifies
`
`the
`
`absorbance
`
`from the blending process of
`
`a
`
`pharmaceutical compound.
`
`[0019]
`
`FIGURE 14 shows what might be an eventual flow-chart of a smart manufacturing
`
`process.
`
`[0020]
`
`FIGURE15Aillustrates the near-infrared reflectance spectrum of wheatflour.
`
`3
`
`Petitioner Apple Inc. — Ex. 1015, p. 3
`
`Petitioner Apple Inc. – Ex. 1015, p. 3
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`OMNIO105PRV
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`[0021]
`
`FIGURE 15B shows the near-infrared absorbance spectra obtained in diffusion
`
`reflectance modefor a series of whole ‘Hass’ avocadofruit.
`
`[0022]
`
`FIGURE 16A is a schematic diagram of the basic elements of an imaging
`
`spectrometer.
`
`[0023]
`
`FIGURE 16B illustrates one example of a typical imaging spectrometer used in
`
`hyper-spectral imaging systems.
`
`[0024]
`
`FIGURE17 showsone example of the Fourier transform infrared spectrometer.
`
`[0025]
`
`FIGURE 18 exemplifies a dual-beam experimental set-up that may be used to
`
`subtract out (or at least minimize the adverse effects of) light source fluctuations.
`
`[0026]
`
`FIGURE 19 illustrates a block diagram or building blocks for constructing high
`
`powerlaser diode assemblies.
`
`[0027]
`
`FIGURE20 showsa platform architecture for different wavelength ranges for an all-
`
`fiber-integrated, high powered, super-continuum light source.
`
`[0028]
`
`FIGURE 21 illustrates one embodiment for a short-wave infrared super-continuum
`
`light source.
`
`[0029]
`
`FIGURE22 showsthe output spectrum from the SWIR SC laser of FIGURE 21 when
`
`about a 10m length of fiber for SC generation is used. This fiber is a single-mode, non-dispersion
`
`shifted fiber that is optimized for operation near 1550nm.
`
`[0030]
`
`FIGURE23illustrates high power SWIR-SC lasers that may generate light between
`
`approximately 1.4-1.8 microns (top) or approximately 2-2.5 microns (bottom).
`
`DETAILED DESCRIPTION
`
`[0031]
`
`As required, detailed embodiments of the present disclosure are described herein;
`
`however,
`
`it is to be understood that the disclosed embodiments are merely exemplary of the
`
`Petitioner Apple Inc. — Ex. 1015, p. 4
`
`Petitioner Apple Inc. – Ex. 1015, p. 4
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`disclosure that may be embodiedin various and alternative forms. The figures are not necessarily to
`
`scale; some features may be exaggerated or minimized to show details of particular components.
`
`Therefore, specific structural and functional details disclosed herein are not to be interpreted as
`
`limiting, but merely as a representative basis for teaching one skilled in the art to variously employ
`
`the present disclosure.
`
`[0032]
`
`One advantage of optical systems is that they can perform non-contact, stand-off or
`
`remote sensing distance spectroscopy of various materials. As an example, optical systems can be
`
`used for identification of counterfeit drugs, detection of illicit drugs, or process control in the
`
`pharmaceutical industry, especially when the sensingis to be done at remote or stand-off distances in
`
`a non-contact, rapid manner.
`
`In general, the near-infrared region of the electromagnetic spectrum
`
`covers between approximately 0.7 microns (700nm) to about 2.5 microns (2500nm). However, it
`
`may also be advantageous to use just the short-wave infrared (SWIR) between approximately 1.4
`
`microns (1400nm) and about 2.5 microns (2500nm). One reason for preferring the SWIR over the
`
`entire NIR may be to operate in the so-called “eye safe” window, which corresponds to wavelengths
`
`longer than about 1400nm. Therefore, for the remainder of the disclosure the SWIR will be used for
`
`illustrative purposes. However,it should be clear that the discussion that follows could also apply to
`
`using the near infrared — NIR -- wavelength range, or other wavelength bands.
`
`[0033]
`
`In particular, wavelengths in the eye safe window may nottransmit downto the retina
`
`of the eye, and therefore, these wavelengths maybeless likely to create permanent eye damage from
`
`inadvertent exposure. The near-infrared wavelengths havethe potential to be dangerous, because the
`
`eye cannot see the wavelengths (as it can in the visible), yet they can penetrate and cause damage to
`
`the eye. Even if a practitioner is not looking directly at the laser beam, the practitioner’s eyes may
`
`receive stray light from a reflection or scattering some surface. Hence, it can always be a good
`
`practice to use eye protection when working around lasers. Since wavelengths longer than about
`
`1400nm are substantially not transmitted to the retina or substantially absorbed in the retina, this
`
`wavelength range is known as the eye safe window. For wavelengths longer than 1400nm, in
`
`general only the cornea of the eye may receive or absorb the light radiation.
`
`Petitioner Apple Inc. — Ex. 1015, p. 5
`
`Petitioner Apple Inc. – Ex. 1015, p. 5
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`OMNIO105PRV
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`[0034]
`
`The SWIR wavelength range may be particularly valuable for identifying materials
`
`based on their chemical composition because the wavelength range comprises overtones and
`
`combination bands for numerous chemical bonds. For example, in the SWIR numerous hydro-
`
`carbon chemical compounds have overtone and combinational bands, along with oxygen-hydrogen
`
`and carbon-oxygen compounds. Thus, gases,
`
`liquids and solids that comprise these chemical
`
`compounds may exhibit spectral
`
`features in the SWIR wavelength range.
`
`In a particular
`
`embodiment, the spectra of organic compounds may be dominated by the C-H stretch. The C-H
`
`stretch fundamental occurs near 3.4 microns,
`
`the first overtone is near 1.7 microns, and a
`
`combination band occurs near 2.3 microns.
`
`[0035]
`
`One embodiment of remote sensing that is used to identify and classify various
`
`materials is so-called “hyper-spectral imaging.” Hyper-spectral sensors maycollect information as a
`
`set of images, where each image represents a range of wavelengths over a spectral band. Hyper-
`
`spectral imaging may deal with imaging narrow spectral bands over an approximately continuous
`
`spectral range. As an example, in hyper-spectral imaging a lamp maybe used asthe light source.
`
`However, the incoherent light from a lamp may spatially diffract rapidly, thereby making it difficult
`
`to perform spectroscopy at stand-off distances or remote distances.
`
`Therefore,
`
`it would be
`
`advantageous to have a broadbandlight source covering the SWIR that may be used in place of a
`
`lamp to identify or classify materials in remote sensing or stand-off detection applications.
`
`[0036]
`
`As used throughout this document, the term “couple” and or “coupled” refers to any
`
`direct or indirect communication between two or more elements, whether or not those elements are
`
`physically connected to one another. As used throughoutthis disclosure, the term “spectroscopy”
`
`means that a tissue or sample is inspected by comparing different features, such as wavelength (or
`
`frequency), spatial location, transmission, absorption, reflectivity, scattering, fluorescence, refractive
`
`index, or opacity.
`
`In one embodiment, “spectroscopy” may mean that the wavelength of the light
`
`source is varied, and the transmission, absorption, fluorescence, or reflectivity of the tissue or sample
`
`is measured as a function of wavelength. In another embodiment, “spectroscopy” may meanthat the
`
`wavelength dependence of the transmission, absorption, fluorescence or reflectivity is compared
`
`between different spatial locations on a tissue or sample. As anillustration, the “spectroscopy” may
`
`Petitioner Apple Inc. — Ex. 1015, p. 6
`
`Petitioner Apple Inc. – Ex. 1015, p. 6
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`OMNIO105PRV
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`be performed by varying the wavelength of the light source, or by using a broadbandlight source
`
`and analyzing the signal using a spectrometer, wavemeter, or optical spectrum analyzer.
`
`[0037]
`
`Asused throughout this document, the term “fiber laser” refers to a laser or oscillator
`
`that has as an output light or an optical beam, wherein at least a part of the laser comprises an optical
`
`fiber. For instance, the fiber in the “fiber laser” may comprise one of or a combination of a single
`
`modefiber, a multi-modefiber, a mid-infrared fiber, a photonic crystal fiber, a doped fiber, a gain
`
`fiber, or, more generally, an approximately cylindrically shaped waveguide or light-pipe.
`
`In one
`
`embodiment, the gain fiber may be doped with rare earth material, such as ytterbium, erbium, and/or
`
`thulium.
`
`In another embodiment, the mid-infrared fiber may comprise one or a combination of
`
`fluoride fiber, ZBLAN fiber, chalcogenide fiber, tellurite fiber, or germanium doped fiber.
`
`In yet
`
`another embodiment, the single mode fiber may include standard single-mode fiber, dispersion
`
`shifted fiber, non-zero dispersion shifted fiber, high-nonlinearity fiber, and small core sizefibers.
`
`[0038]
`
`As used throughout
`
`this disclosure,
`
`the term “pump laser” refers to a laser or
`
`oscillator that has as an output light or an optical beam, wherein the output light or optical beam is
`
`coupled to a gain medium to excite the gain medium, which in turn may amplify another input
`
`optical signal or beam.
`
`In one particular example, the gain medium may be a dopedfiber, such as a
`
`fiber doped with ytterbium, erbium and/or thulium.
`
`In one embodiment, the “pump laser’ may be a
`
`fiber laser, a solid state laser, a laser involving a nonlinear crystal, an optical parametric oscillator, a
`
`semiconductor laser, or a plurality of semiconductor lasers that may be multiplexed together.
`
`In
`
`another embodiment, the “pump laser” may be coupled to the gain medium byusing a fiber coupler,
`
`a dichroic mirror, a multiplexer, a wavelength division multiplexer, a grating, or a fused fiber
`
`coupler.
`
`[0039] and_orAs used throughout this document, the term “super-continuum’”
`
`
`
`
`
`
`
`
`
`
`
`
`
`“supercontinuum” and or “SC” refers to a broadbandlight beam or output that comprises a plurality
`
`of wavelengths.
`
`In a particular example, the plurality of wavelengths may be adjacent to one-
`
`another, so that the spectrum of the light beam or output appears as a continuous band when
`
`measured with a spectrometer. In one embodiment, the broadband light beam may have a bandwidth
`
`of at
`
`least 10nm.
`
`In another embodiment,
`
`the “super-continuum” may be generated through
`
`Petitioner Apple Inc. — Ex. 1015, p. 7
`
`Petitioner Apple Inc. – Ex. 1015, p. 7
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`OMNIO105PRV
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`nonlinear optical interactions in a medium, such as an optical fiber or nonlinear crystal.
`
`For
`
`example,
`
`the “super-continuum” may be generated through one or a combination of nonlinear
`
`activities such as four-wave mixing, parametric amplification,
`
`the Raman effect, modulational
`
`instability, and self-phase modulation.
`
`[0040]
`
`As used throughout this disclosure, the terms “optical light’ and or “optical beam”
`
`and or “light beam” refer to photons or light transmitted to a particular location in space. The
`
`“optical light’ and or “optical beam” and or “light beam” may be modulated or unmodulated, which
`
`also means that they may or may not contain information.
`
`In one embodiment, the “optical light”
`
`and or “optical beam” and or “light beam” may originate from a fiber, a fiber laser, a laser, a light
`
`emitting diode, a lamp, a pumplaser,or a light source.
`
`[0041]
`
`As used throughout
`
`this disclosure,
`
`the term “remote sensing” may include the
`
`measuring of properties of an object from a distance, without physically sampling the object, for
`
`example by detection of the interactions of the object with an electromagnetic field.
`
`In one
`
`embodiment,
`
`the electromagnetic field may be in the optical wavelength range,
`
`including the
`
`infrared or SWIR. One particular form of remote sensing may be stand-off detection, which may
`
`range exemplary from non-contact up to hundreds of meters away.
`
`IDENTIFICATION OF COUNTERFEIT DRUGS
`
`[0042]
`
`Pharmaceutical counterfeiting is a growing and significant issue for the healthcare
`
`community as well as the pharmaceutical industry worldwide. As a result of counterfeiting, users
`
`may be threatened by substandard drug quality or harmful ingredients, and legitimate companies
`
`may lose significant revenues.
`
`The definition for “counterfeit drug” by the World Health
`
`Organization was as follows: “A counterfeit medicine is one which is deliberately and fraudulently
`
`mislabeled with respect to identity and/or source. Counterfeiting can apply to both branded and
`
`generic products and counterfeit products may include products with the correct ingredients or with
`
`the wrong ingredients, without active ingredients, with insufficient active ingredient or with fake
`
`packaging.” Later this definition was slightly modified, “Counterfeiting in relation to medicinal
`
`products means the deliberate and fraudulent mislabeling with respect to the identity, composition
`
`Petitioner Apple Inc. — Ex. 1015, p. 8
`
`Petitioner Apple Inc. – Ex. 1015, p. 8
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`OMNIO105PRV
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`and/or source of a finished medicinal product, or ingredient for the preparation of a medicinal
`
`product.”
`
`[0043]
`
`A rapid screening technique such as near-infrared or SWIR spectroscopy could aid in
`
`the search for and identification of counterfeit drugs.
`
`In particular, using a non-lamp based light
`
`source could lead to contact-free control and analysis of drugs.
`
`In a particular embodiment, remote
`
`sensing, stand-off detection, or hyper-spectral
`
`imaging may be used for process control or
`
`counterfeit drug identification in a factory or manufacturing setting, or in a retail, wholesale, or
`
`warehouse setting.
`
`In one embodiment, the light source for remote sensing may direct the light
`
`beam toward the region of interest (e.g., conveyor belt, stocking shelves, boxes or cartons, etc), and
`
`the diffuse reflected light may then be measured using a detection system. Various kinds of SWIR
`
`light sources will be discussed later in this disclosure. The detection system may comprise, in one
`
`embodiment, a spectrometer followed by one or more detectors.
`
`In another embodiment,
`
`the
`
`detection system may be a dispersive element
`
`(examples include prisms, gratings, or other
`
`wavelength separators) followed by one or more detectors or detector arrays.
`
`In yet another
`
`embodiment, the detection system may comprise a Fourier transform infrared spectrometer. These
`
`are merely specific examples of the detection system, but combinations of these or other detection
`
`systems mayalso be used and are contemplated within the scope ofthis disclosure.
`
`[0044]
`
`For monitoring drugs, the SWIR light source and the detection system could be used
`
`in transmission, reflection, fluorescence, or diffuse reflection. Also, different system configurations
`
`may also be used and are included in the scope of this disclosure. For example, the light source and
`
`detection system maybe placed in a fixed location, and for reflection the light source and detectors
`
`may beclose to one another, while for transmission the light source and detectors maybeat different
`
`locations. The region of interest may be surveyed, and the light beam may also be scanned to cover
`
`an area larger than the light source beam. In yet another embodiment, the system could be placed on
`
`a vehicle such as an automobile or a truck, or the light source could be placed on one vehicle, while
`
`the detection system is on another vehicle. If the light source and detection system are compact and
`
`lightweight, they might even be carried by a person in the field, either in their hands or in a
`
`backpack.
`
`Petitioner Apple Inc. — Ex. 1015, p. 9
`
`Petitioner Apple Inc. – Ex. 1015, p. 9
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`OMNIO105PRV
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`[0045]
`
`Another advantage of using the near-infrared or SWIR is that most drug packaging
`
`materials are at least partially transparent in this wavelength range, so that drug compositions may be
`
`detected and identified through the packaging non-destructively. As an example, SWIR light could
`
`be used to see through plastics, since the signature for plastics can be subtracted off and there are
`
`large wavelength windows wherethe plastics are transparent. FIGURE1illustrates the absorbance
`
`100 for two commonplastics: polyethylene 101 and polystyrene 102. Because of the hydro-carbon
`
`bonds, there are absorption features near 1.7 microns and 2.2-2.5 microns.
`
`In general, the absorption
`
`bandsin the near infrared are due to overtones and combination bandsfor various functional group
`
`vibrations, including signals from C-H, O-H, C=O, N-H, -COOH,and aromatic C-H groups.
`
`It may
`
`be difficult to assign an absorption band to a specific functional group due to overlapping of several
`
`combinations and overtones.
`
`However, with advancements
`
`in computational power and
`
`chemometrics or multivariate analysis methods, complex systems may be better analyzed.
`
`In one
`
`embodiment, using software analysis tools the absorption spectrum may be converted to its second
`
`derivative equivalent. The spectral differences may permit a fast, accurate, non-destructive and
`
`reliable identification of materials.
`
`Although particular derivatives
`
`are discussed, other
`
`mathematical manipulations may be used in the analysis, and these other techniques are also
`
`intended to be covered bythis disclosure.
`
`[0046]
`
`Spectroscopy in the near-infrared or SWIR maybesensitive to both the chemical and
`
`physical nature of the sample composition and may be performed rapidly with minimal sample
`
`preparation.
`
`For example, near-infrared or SWIR spectroscopy may be used to study the
`
`homogeneity of powder
`
`samples, particle
`
`size determinations, product
`
`composition,
`
`the
`
`determination of the concentrations and distribution of components in solid tablets and content
`
`uniformity, among other applications.
`
`In yet other embodiments, applications include tablet
`
`identification, determination of moisture, residual solvents, active ingredient potency, the study of
`
`blending operations, and the detection of capsule tampering.
`
`[0047]
`
`FIGURE2 illustrates one example of the difference in near-infrared spectrum 200
`
`between an authentic tablet and a counterfeit tablet. Two grades of film coated tablets comprising
`
`drugs were investigated: curve 201 is the genuine drug, while 202 is a counterfeit drug. These two
`
`grades of capsules have noticeably different contents, and the differences are apparent in the near-
`
`10
`
`Petitioner Apple Inc. — Ex. 1015, p. 10
`
`Petitioner Apple Inc. – Ex. 1015, p. 10
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`OMNIO105PRV
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`infrared or SWIR spectra.
`
`In some cases the differences may not be as distinct. For these cases,
`
`more signal processing may be necessary to distinguish between samples.
`
`[0048]
`
`In another embodiment, it may be advantageousto take a first, second or higher order
`
`derivative to elucidate the difference between real and counterfeit drugs. For example, FIGURE 3
`
`showsthe secondderivative 300 of the spectral comparison of Prozac 301 and a similarly formulated
`
`generic 302, which had a fluoxetine hydrochloride (10mg). Although the reflectance curves from
`
`the two samples are close and, therefore, difficult to distinguish, the second derivative of the data
`
`helps to bring out the differences more clearly. Although a second derivative is used in this
`
`example, any numberof signal processing algorithms and methods may be used, and these are also
`
`intended to be covered by this disclosure. For example, partial least square algorithms, multivariate
`
`data analysis, principal component analysis, or chemometric software may be implemented without
`
`departing from the scope of this disclosure.
`
`[0049]
`
`In yet another embodiment, near-infrared or SWIR spectroscopy may be used to
`
`measure and calibrate various pharmaceutical formulations based on the active pharmaceutical
`
`ingredients and excipients. An excipient may be a pharmacologically inactive substance used as a
`
`carrier for the active ingredients of a medication.
`
`In some cases, the active substance may not be
`
`easily administered and/or absorbed by the human body; in such cases the active ingredient may be
`
`dissolved into or mixed with an excipient. Also, excipients are also sometimes used to bulk up
`
`formulations that contain very potent active ingredients,
`
`to allow for convenient and accurate
`
`dosage.
`
`In addition to their use in the single-dosage quantity, excipients can be used in the
`
`manufacturing process to aid in the handling of the active substance concerned.
`
`[0050]
`
`FIGURE 4 shows an example of the near-infrared spectra 400 for different pure
`
`components of a studied drug. The spectrum for the active pharmaceutical ingredient (API) 401 is
`
`plotted, along with the spectra for five different excipients 402, 403, 404, 405 and 406. Each
`
`spectrum has been baseline shifted to avoid overlapping. The near-infrared spectra have been
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`obtained by averaging the spectra of each pixel of an area of a hyper-spectral image. As FIGURE 4
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`shows, each of the chemical compositions have a distinct spectrum, and the composition of a drug
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`may be decomposedinto its constitutive ingredients. These are just some examples of how near-
`
`11
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`Petitioner Apple Inc. — Ex. 1015, p. 11
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`Petitioner Apple Inc. – Ex. 1015, p. 11
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`OMNIO105PRV
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`infrared or SWIR spectroscopy may be applied to counterfeit drug detection, but other methods and
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`analysis techniques may also be used without departing from the scope of this disclosure. As one
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`other example, once the active pharmaceutical ingredient and the excipients spectral distribution of a
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`drug formulation are understood, feedback may be provided of this information to the drug
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`developmentstages.
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`RAPID SCREENING FORILLICIT DRUGS
`
`[0051]
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`Thus, FIGURES 2-4 showthat near-infrared or SWIR spectroscopy may be used to
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`identify counterfeit drugs. More generally, various materials including illicit drugs, explosives,
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`fertilizers, vegetation, and paints have features in the near-infrared and SWIR that can be used to
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`identify the various samples, and these applications are also intended to be within the scope of this
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`disclosure. Although stronger features may be found in the mid-infrared, the near-infrared may be
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`easier to measure due to higher quality detection systems, more mature fiber optics and light sources,
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`and transmission through atmospheric transmission windows. Because of these distinct spectral
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`signatures,
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`these materials could also be detected using active remote sensing, hyper-spectral
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`imaging, or near-infrared or SWIR spectroscopy. As just another example, illicit drugs may be
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`detectable using remote sensing, hyper-spectral imaging, or near-infrared spectroscopy. FIGURE 5
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`shows the mid-waveinfrared and long-waveinfrared absorption spectra 500 for variousillicit drugs.
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`The absorbance for cocaine 501, methamphetamine 502, MDMA(ecstasy) 503, and heroin 504 are
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`plotted versus wavelength from approximately 2.5-20 microns.
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`Although the fundamental
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`resonances for these drugs may lie in the longer wavelength regions,
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`there are corresponding
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`overtones and combination bands in the SWIR and near-infrared wavelength range. Therefore, the
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`active remote sensing, hyper-spectral imaging, or near-infrared or SWIR spectroscopy techniques
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`described herein mayalso be applicable to detectingillicit drugs from aircraft, vehicles, or hand held
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`devices.
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`[0052]
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`The diffuse reflectance technique may be useful with near-infrared or SWIR
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`spectroscopy for rapid identification of illegal drugs due to simple handling and simple use of a
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`search data library created using near-infrared diffuse reflectance.
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`For instance, FIGURE 6
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`illustrates the absorbance 600 versus wavelength in the near-infrared region for four classes ofillegal
`
`12
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`Petitioner Apple Inc. — Ex. 1015, p. 12
`
`Petitioner Apple Inc. – Ex. 1015, p. 12
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`OMNIO105PRV
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`drugs. In particular, the spectra are shown for methamphetamine (MA) 601, amphetamine (AP) 602,
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`MDMA(street name: ecstasy) 603, and MDA (street name:
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`the love drug) 604. Eachofthe illegal
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`drugs have unique spectral features in the near-infrared and SWIR. Also, comparing the mid-
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`infrared spectrum for MDMA (503 in FIGURE5) with the near-infrared spectrum for MDMA (603
`
`in FIGURE6), it seems clear that the near-infrared region shows overtones and combination bands
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`that should be discernible. Referring to FIGURE 6, sample identification may be accomplished by
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`using the region (indicated by the arrows) where the spectral absorptions may provide specific peaks
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`depending on the drug component.
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`[0053]
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`In another embodiment, FIGURE 7 shows the diffuse reflectance near-infrared
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`spectrum 700 of heroin samples. Heroin, the 3,6-diacetyl derivative of morphine (hence diacetyl-
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`morphine) is an opiate drug synthesized from morphine, which is usually a naturally occurring
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`substance extracted from the seedpod of certain varieties of poppy plants.
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`In particular, 701 is the
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`near-infrared spectrum for an illicit street drug sample, while 702 is the spectra for a pure heroin
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`standard. The difference between the spectra may arise at least in part from cutting agents. The
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`inset 703 showsthe molecular structure for heroin. As in the other examples, the absorption in the
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`near-infrared range is caused by overtone and combination vibrations of O-H, C-H, N-H and C=O
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`groups, which exhibit their fundamental molecular stretching and bending absorption in the mid-
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`infrared range (c.f.,
`
`the mid-infrared spectrum for heroin is shown 504 in FIGURE 5). These
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`overtone and combination bands do not behave in a simple way, making the near-infrared spectra
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`complex and harder to directly interpret. Also, although the near-infrared signatures may be weaker
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`in magnitude, they are probably easier to detect in the near-infrared, and the sample preparation may
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`also be much simpler in the near-infrared. Moreover, for remote sensing, the near-infrared may be
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`preferable because of atmospheric transmission windows between approximately 1.4-1.8 microns
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`and 2-2.5 microns.
`
`[0054]
`
`Pure heroin may be a white powderwith a bitter taste that is rarely sold on the streets,
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`while illicit heroin may be a powdervarying in color from white to dark brown due to impurities left
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`from the manufacturing process or the presence of additives. The purity of street heroin may also
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`vary widely, as the drug can be mixed with other white powders. The impurity of the drug may
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`often makeit difficult to gauge the strength of the dosage, which runsthe risk of overdose. One nice
`
`13
`
`Petitioner Apple Inc. — Ex. 1015, p. 13
`
`Petitioner Apple Inc. – Ex. 1015, p. 13
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`OMNIO105PRV
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`feature of near-infrared or SWIR spectroscopy is that
`
`the technique may be used in a non-
`
`destructive, non-contact manner to determine rapidly the concentration of compoundspresent in
`
`complex samples at percentage levels with very little sample preparation.
`
`In a particular
`
`embodiment, FIGURE 8 illustrates the diffuse reflectance near-infrared spectra 800 of different
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`seized illicit drugs containing heroin (between 10.7 and 21.8%) compared with the spectrum of pure
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`heroin 801. Curve 802 is for 21.8% by weight, curve 803 is 13.2% by weight, curve 804 is 17% by
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`weight, and curve 805 is 10.7% by weight of heroin. The spectra have been shifted along the
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`vertical axis to better illustrate the differences.
`
`[0055]
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`Although quite complex in the near-infrared, it may be possible to identify from the
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`pure heroin near-infrared spectrum (801 in FIGURE8 or 702 in FIGURE7) the main wavelengths
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`related to the m